The phenotypic spectrum of SCN2A-related epilepsy Reynolds, Claire; King, Mary D.; Gorman, Kathleen M.
European journal of paediatric neurology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Volume:
24
Journal Article
Peer reviewed
Pathogenic variants in SCN2A are reported in a spectrum of neurodevelopmental disorders including developmental and epileptic encephalopathies, benign familial neonatal-infantile seizures, episodic ...ataxia, and autism spectrum disorder and intellectual disability with and without seizures. To date, more than 300 patients with SCN2A variants have been published, the majority presenting with epilepsy. Large cohort studies and variant-specific electrophysiology, have enabled the delineation of different SCN2A-epilepsy phenotypes, phenotype-genotype correlations, prediction of pharmacosensitivity to sodium channel blockers and long-term prognostication for clinicians and families. Herein, we summarise the core phenotypes of SCN2A-related epilepsy, genotype-phenotype correlations, response to medication and future research.
•SCN2A is one of the commonest causes of neurodevelopmental disorders, accounting for 1% of all epileptic encephalopathies.•SCN2A phenotypes include BFNIS, developmental and epileptic encephalopathies and ASD/intellectual disability with epilepsy.•Genotype-phenotype correlations and electrophysiology may predict response to sodium channel blockers and seizure outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes ...as well as emerging diagnostic strategies. In this single‐center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole‐exome sequencing (WES), targeting a list of 137 epilepsy‐associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible. Infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We identified disease‐causing variants in 11 children (22%) in the following genes: STXBP1 (n = 3), KCNB1 (n = 2), KCNT1, SCN1A, SCN2A, GRIN2A, DNM1, and KCNA2. We also identified two further variants (in GRIA3 and CPA6) in two children requiring further investigation. Eleven variants were de novo, and in one paternal testing was not possible. Phenotypes were broadened for some variants identified. This study demonstrates that WES is a clinically useful screening tool for previously investigated unexplained EOEE and allows for reanalysis of data as new genes are being discovered. Detailed phenotyping allows for expansion of specific gene disorders leading to epileptic encephalopathy and emerging sub‐phenotypes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Status dystonicus: a practice guide Allen, Nicholas M; Lin, Jean‐Pierre; Lynch, Tim ...
Developmental medicine and child neurology,
February 2014, Volume:
56, Issue:
2
Journal Article
Peer reviewed
Open access
Status dystonicus is a rare, but life‐threatening movement disorder emergency. Urgent assessment is required and management is tailored to patient characteristics and complications. The use of ...dystonia action plans and early recognition of worsening dystonia may potentially facilitate intervention or prevent progression to status dystonicus. However, for established status dystonicus, rapidly deployed temporizing measures and different depths of sedation in an intensive care unit or high dependency unit are the most immediate and effective modalities for abating life‐threatening spasms, while dystonia‐specific treatment takes effect. If refractory status dystonicus persists despite orally active anti‐dystonia drugs and unsuccessful weaning from sedative or anaesthetic agents, early consideration of intrathecal baclofen or deep brain stimulation is required. During status dystonicus, precise documentation of dystonia sites and severity as well as the baseline clinical state, using rating scales and videos is recommended. Further published descriptions of the clinical nature, timing of evolution, resolution, and epidemiology of status dystonicus are essential for a better collective understanding of this poorly understood heterogeneous emergency. In this review, we provide an overview of the clinical presentation and suggest a management approach for status dystonicus.
What this paper adds
An overview of status dystonicus and a practical approach to the management of status dystonicus and ‘pre‐status dystonicus’
.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Next-generation sequencing has enhanced discovery of many disease-associated genes in previously unexplained epilepsies, mainly in developmental and epileptic encephalopathies and familial ...epilepsies. We now classify these disorders according to the underlying molecular pathways, which encompass a diverse array of cellular and sub-cellular compartments/signalling processes including voltage-gated ion-channel defects. With the aim to develop and increase the use of precision medicine therapies, understanding the pathogenic mechanisms and consequences of disease-causing variants has gained major relevance in clinical care. The super-family of voltage-gated potassium channels is the largest and most diverse family among the ion channels, encompassing approximately 80 genes. Key potassium channelopathies include those affecting the KV, KCa and Kir families, a significant proportion of which have been implicated in neurological disease. As for other ion channel disorders, different pathogenic variants within any individual voltage-gated potassium channel gene tend to affect channel protein function differently, causing heterogeneous clinical phenotypes. The focus of this review is to summarise recent clinical developments regarding the key voltage-gated potassium (KV) family-related epilepsies, which now encompasses approximately 12 established disease-associated genes, from the KCNA-, KCNB-, KCNC-, KCND-, KCNV-, KCNQ- and KCNH-subfamilies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective The purpose of this study was to determine risk factors that are associated with hypoxic ischemic encephalopathy (HIE). Study Design This was a case-control study that included newborn ...infants with HIE who were admitted to the hospital between January 2001 and December 2008. Two control newborn infants were chosen for each case. Logistic regression and classification and regression tree (CART) analysis that compared control infants and cases with grade 1 HIE and control infants and cases with grades 2 and 3 HIE was performed. Results Two hundred thirty-seven cases (newborn infants with grade 1 encephalopathy, 155; newborn infants with grade 2 encephalopathy, 61; newborn infants with grade 3 encephalopathy, 21) and 489 control infants were included. Variables that were associated independently with HIE included higher grade meconium, growth restriction, large head circumference, oligohydramnios, male sex, fetal bradycardia, maternal pyrexia and increased uterine contractility. CART analysis ranked high-grade meconium, oligohydramnios, and the presence of obstetric complications as the most discriminating variables and defined distinct risk groups with HIE rates that ranged from 0–86%. Conclusion CART analysis provides information to help identify the time at which intervention in labor may be of benefit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Next-generation sequencing has enhanced discovery of many disease-associated genes in previously unexplained epilepsies, mainly in developmental and epileptic encephalopathies and familial ...epilepsies. We now classify these disorders according to the underlying molecular pathways, which encompass a diverse array of cellular and sub-cellular compartments/signalling processes including voltage-gated ion-channel defects. With the aim to develop and increase the use of precision medicine therapies, understanding the pathogenic mechanisms and consequences of disease-causing variants has gained major relevance in clinical care. The super-family of voltage-gated potassium channels is the largest and most diverse family among the ion channels, encompassing approximately 80 genes. Key potassium channelopathies include those affecting the K
, K
and K
families, a significant proportion of which have been implicated in neurological disease. As for other ion channel disorders, different pathogenic variants within any individual voltage-gated potassium channel gene tend to affect channel protein function differently, causing heterogeneous clinical phenotypes. The focus of this review is to summarise recent clinical developments regarding the key voltage-gated potassium (K
) family-related epilepsies, which now encompasses approximately 12 established disease-associated genes, from the KCNA-, KCNB-, KCNC-, KCND-, KCNV-, KCNQ- and KCNH-subfamilies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
7.
Paroxysmal Movement Disorders Harvey, Susan; King, Mary D.; Gorman, Kathleen M.
Frontiers in neurology,
06/2021, Volume:
12
Journal Article
Peer reviewed
Open access
Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ...ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (
RHOBTB2, TBC1D24
), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in
PRRT2
but also variants identified in
PNKD, SCN8A, and SCL2A1
. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.
Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA ...repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established.
One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians.
We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Mutations in KCNQ2 and KCNQ3 were originally described in infants with benign familial neonatal seizures (BFNS). Recently, KCNQ2 mutations have also been shown to cause epileptic ...encephalopathy. This report describes three infants carrying abnormalities of KCNQ2 and one infant with a KCNQ3 mutation. The different KCNQ2 abnormalities led to different phenotypes and included a novel intragenic duplication, c.419_430dup, in an infant with BFNS, a 0.761Mb 20q13.3 contiguous gene deletion in an infant with seizures at 3 months, and a recurrent de novo missense mutation c.881C>T in a neonate with “KCNQ2‐encephalopathy.” The mutation in KCNQ3, c.989G>A, was novel and occurred in an infant with BFNS. KCNQ‐related seizures often present with tonic/clonic manifestations, cyanosis, or apnea. Certain genotype–phenotype correlations help predict outcome. Similarly affected family members suggests benign familial “KCNQ‐related” epilepsy, whereas neonatal seizures with unexplained multifocal epileptiform discharges or burst suppression on electroencephalography, and acute abnormalities of the basal ganglia/thalami are suggestive of KCNQ2‐encephalopathy, which is often sporadic. 20q13.33 contiguous gene deletion encompassing KCNQ2 may harbor atypical features depending on deletion size. Although the phenotype often guides direct targeted gene testing in these conditions, array CGH should also be considered in suspected sporadic or atypical familial cases to diagnose 20q13.33 deletion.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Status dystonicus in childhood Lumsden, Daniel E; King, Mary D; Allen, Nicholas M
Current opinion in pediatrics
29, Issue:
6
Journal Article
Peer reviewed
Dystonia is a common paediatric neurological condition. At its most severe, dystonia may lead to life-threatening complications, a state termed status dystonicus. This review provides an update on ...the definition, causes, management and outcome of childhood status dystonicus.
High-quality studies in childhood status dystonicus are lacking, though an increasing number of case series have been published. Status dystonicus appears to occur more frequently in children compared with adults, with a clear precipitant identified in around two-thirds of cases. Although febrile illness remains the commonest trigger for status dystonicus, unplanned interruption to deep brain stimulation (DBS) is increasingly reported as a precipitant. In parallel with this, neurosurgical intervention for status dystonicus appears to have become more widely used, though optimum timing and patient selection remains unclear. In most cases, a multistaged approach is required; we propose an 'ABCD' approach - Addressing precipitants, Beginning supportive measures, Calibrating sedation and Dystonia specific medications. Outcomes following status dystonicus appear to have slightly improved in recent years, potentially as a consequence of increasing use of DBS, though mortality has remained around 10%.
Future work is needed to inform evidence-based guidelines for the management of status dystonicus. One of many pressing questions is the precise indication, and timing of interventions such as DBS.
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